Derivatives of heterocyclic compounds



United States lce 2,996,533

Patented Aug. 15, 1961 the identity of the acid being of little importance pro- 2,996,503 vided it is non-toxic. The salts are therefore considered DERIVATIVES F HETEROCYCLIG to be equivalent to the bases.

COMPOUNDS The novel process which has been developed to make James sprague and Edward Engelhardtfi i 5 the compounds of this invention constitutes another fea- Valley, and Marcia E. Christy, Cioverdale Park, Cold' tothi ossthe mar,Pa., assignors to Merck& C0.,Inc., RahWay,N.J., ture of this mventlon Accor mg 8 pr Ce Grignard reagent is prepared from the appropriate 3- il ri ei tf f 195s, Ser. No. 536,274 tertiawemimpmpyl in The f 1 C (CL 2 0 2 7 1 sired thiaxanthone derivative then is added to the reaction 10 mixture. After hydrolysis of the Grignard adduct, the This invention relates to new chemical compounds and 'y P py 10 hlfdroxythlaxanflflene to a novel method for preparing h I particular h is isolated and dehydrated to the desired 10-(3-tert1aryinvention relates to new thiaxanthene derivatives having p pyl f that can be isolated as the following general formula n id ddltlon Salt. I s Previous workers have employed ether and mixtures 6 5 4 of ether and benzene as solvents in the preparation of X I I X basically substituted Grignard reagents. In the case of Q 10 1 3-dimethylaminopropyl chloride the Grignard reagent is h insoluble in ether and the separation of the solid stops CHCH CH N the reaction. While it has been discovered that the desired end product can be obtained by carefully controlled portionwise addition of the ketone, it is much more convenient and considerably less time consuming to carry out the process by operating in tetrahydnofuran which permits the formation of the organomagnesium compound to go to completion prior to the addition of "the ketone.

The new compounds which are unsymmetrically substituted in the thiaxanthene nucleus may be obtained as a mixture of geometric isomers. When more than one and non-toxic acid addition salts thereof, wherein X and X respectively represents hydrogen, halogen particularly chlorine or bromine, a lower alkyl radical for example a straight or branched chain alkyl radical having from 1 to about 4 carbon atoms, and a lower alkoxy radical preferably having a straight or branched alkyl chain with from 1 to about 4 carbon atoms; and

R isomer are isolated from a reaction mixture, they are designated in this application as the alpha and beta isomer in the order of isolation. While the mixture exhibits anti-emetic properties, in some instances the activity may is a tertiary amino gnoup and particularly a tertiary amino be greater in one pure isomer than the other.

group selected from the dilowerelkylamino. -pip ridyl. This reaction can be schematically illustrated as l-pyrrolidyl or 4-morpholinyl groups. One or more of follows:

R CH-CH2CH:N/

R! the hydrogens attached to the propylidene side chain can The dehydration can be effected by known procedures be substituted by a lower alkyl group provided the total employing known dehydrating agents. Dehydrating number of carbons in all substituent alkyl groups does agents which have been found especially useful are acetyl not exceed four. When one or more of the propylidene chloride, thionyl chloride and acetic anhydride. Other hydrogens is substituted by an alkyl group, one of the dehydrating agents as potassium bisulfate, concentrated alkyl substituents can be linked with R to form a heterohydrochloric acid and the like, can also be used. Solvents cyclic ring with.the nitrogen atom. which are well adapted to the requirements of this step The compounds of this invention have been found to when acetyl chloride or a similar dehydrating agent is be valuable therapeutic agents particularly because of employed are chloroform and methylene chloride. their anti-emetic properties. For physiological purposes, The new compounds and the improved process for these substances are conveniently administered as salts, making them will be described in more detail in the fol- 3 lowing illustrative examples. Methods, other than the improved process which constitutes a feature of this invention, that can be employed in making the novel compounds will also be described in the examples.

EXAMPLE 1 I-(3-dimethylaminopropylidene)-thiaxanthene hydrogen oxalate Magnesium turnings, 2.8 g. (0.115 g. atom), was placed a in a flask fitted with a mercury sealed stirrer, reflux condenser and a dropping funnel. The appa'ratu s was flushed with dry nitrogen and protected from atmospheric moisture by means of a drying tube. Anhydrous ether (dried over calcium hydride), 50 ml., added followed by half of 1.25 g. (0.0115 mole) of ethyl bromide. The remainder of the ethyl bromide was added to a solution of 14.0 g. (0.115 mole) of 3-dirnethylaminopropyl chloride in 15 ml. of ether and 35 ml. of benzene. This solution was added to the stirred magnesium-ether mixturein porti ons over a period ,of 1 hour. The mixture then was stirred at reflux for 1 /2 hours. The reaction mixture, containing an insoluble colorless solid and unreacted magnesium, was cooled to room temperature. Thiaxanthone, 21.2 g. (0.1 mole) was pulverized and added to the stirred reaction mixture in portions over a period of 15 minutes. The heat liberated was suificient to induce refluxing, the solid disappeared and a colorless solid began to separate. The solid became yellow and the reaction mixture became more difiicult to stir. Benzene, 100 ml. was added as the addition of the ketone was completed. The reaction mixture was then refluxed and stirred for 2 hours, then cooled in ice and treated with 50 ml. of water. After warming till the solvent was at reflux, the mixture was filtered, and the filter cake washed with hot benzene. The organic layer was separated and extracted with 3 N hydrochloric acid until the aqueous layer was no longer colored (red). The acid extract was made basic and the yellow oil that separated extracted into ether. The ether extract was washed with water, dried over sodium sulfate and the ether evaporated. The residue, a viscous yellow oil, weighed 12.5 g.', and was 10-(3-dir'nethylaminopropylidene) -thiaxanthene.

A portionof the base was converted to the hydrogen oxalate that melted at 155'157 C. after three recrystallizations from absolute alcohol.

Analysis:-Calculated for C H NS-C H O C, 64.67; H, 5.70; N, 3.77. Found: C, 65.10; H, 5.90; N, 3.82.

EXAMPLE 2 2-chloro 10-(3-dimethyldhdnoproylidene') thirlxmltizeize hydrochloride tep A. Magnesium turnings, 4.86 g. (0.2 g. atom), placed in a 500 ml. reaction flask fitted as described in Example 1. Tetra hydrofuran, 50 ml., and calcium hydride, 500 -mg., were added. Ethyl bromide, 2.18 g., and a crystal of iodine then were added. A vigorous reaction set in that evolved suflicient heat to induce refluxing. After minutes, a solution of 3-dimethylaminopropyl chloride (dried over calcium hydride) in 50 m1. of tetrahydrofurau was added to the refluxing solution at such a rate that gentle refluxing was maintained. The addition required 25 minutes. The reaction mixture was stirred at reflux for an additional 30 minutes when nearly all of the magnesium had dissolved and determination of magnesium in an aliquot of the solution showed that an 82% yield of Grignard reagent had been obtained. The reaction mixture was cooled in an ice bath and stirred while 24.67 g. (0.1 mole) of 2-chlorothiaxanthone was added over a period of minutes. The reactionwas stirred at room temperature for 30 minutes then allowed to stand over night in the refrigerator. Theten'ahydroevaporated at 50 C. under reduced pressure. Benzene, 150 au.,'was 'added to the residue. The mixture 7 hydrolysed in the cold by the dropwise addition of "50 mi. of Water. The layer separated by 4 decantation and the gelatinous precipitate washed with two ml. portions of benzene. The precipitate then was mixed with diatomaceous earth, collected on a filter and washed with water and extracted with two 100 ml. portions of boiling benzene. The aqueous filtrate was extracted with 50 ml. of benzene, the combined benzene extracts washed with water and evaporated to dryness under reduced pressure. The crystalline residue, M.P. l40-147 C., weighed 30.8 g. Recrystallization from a mixture of benzene and hexane gave 27.6 g. (83%) of 2-chloro-10-(3-dimethylaminopropyl)-10hydroxythiaxanthene, M.P. 152-154 C. Analytically pure material from another experiment melted at 15 3-,-154 C.

Analysis:-Calculated for C H ONClsz C, 64.75; H, 6.04; N, 4.20. Found: C, 64.80; H. 5.95; N, 4.20.

Step B.-3.34 g. (-0.01 mole) of the thus obtained 2- chl'oro 10 (3 dimethylaminopropyl) 10 hydroxythiaxanthene was dissolved in 15 ml. of dry, alcohol-free chloroform. Acetyl chloride, 2.36 g. (0.03 mole), was added and the clear yellow solution was refluxed for one hour in a system protected by a drying tube. The solvent then was evaporated on the steam-bath under reduced pressure and the residue dissolved in absolute alcohol. The hydrochloride of 2 chloro l0 (3 dimethylaminopropylidene)thiaxanthene was precipitated by the cau- EXAMPLE 3 a-lsomer of 2-chloro-10-(3dimethylaminopropylidene)- rhiaxanthene hydrochloride The hydrochloride, obtained as described in Example 2 (step B), 35.23 g. (0.1 mole), was dissolved in 200 ml. of water. The solution was made basic with 50 ml. of 10 N sodium hydroxide and the mixture extracted with three 100 ml. portions of benzene. The combined benzene extractswere washed with 50 of water in two portions and the solvent evaporated on the steambath under reduced pressure. The viscous yellow oily base weighed 31.14 g. (99%). The base was stored in the dark at room temperature for 11 days. During this time the a-isomer separated in the form of pale yellow crystals. The semisolid mixture was triturated with 50 ml. of petroleuin ether (SO-60 C.) and the insoluble solid collected and recrystallized repeatedly from hexanepetroleum ether mixtures and alcohol-water mixtures until a constant M.P. of 98-99 C. was attained. The a-isomer of 2 chloro 1 0 (3 dimethylaminopropylidene)- thiaxanthene then was converted to the hydrochloride that melted at 21l.52l2.5 C. (dec.).

Analysis:Calculated for C H NClS-HCl: N, 3.97. Found: N, 3.99.

EXAMPLE 4 ,B-Isomer of 2-chl0ro-10- (3-dimethylaminopropyIidene)- thiaxanthene hydrochloride The petroleum ether filtrate obtained in Example 3 was cooled to 15 C. and the ,:oily crystals that separated removed. Evaporation of the solvent from the filtrate left 14.96 g. of a deep yellow oily residue. This base, 2 chloro 10 (3 dimethylaminopropylidene)- thiaxanthene, was converted to the hydrogen oxalate that melted at 1885-1895 C. after repeated recrystallization from alcohol-water mixtures. The base then was liberated from the oxalate and converted to the hydrochloride that melted at 2055-2065 C. after crystallization from a mixture of absolute alcohol and amuse ether.

AhalySis.'-Calculated for C H NClS'HCl: N, 3.97. Fdundz N,.'3."97.

EXAMPLE 5 2-bromo-1 0- (3-dimethylaminopropylidene) thiaxanthene hydrochloride By replacing the 2-chlorothiaxanthone used in Example 2 by an equimolecular quantity of 2-bromothiaxanthone, and following substantially the same procedures described in steps A and B thereof, there was obtained 2-bromo-10- (3 dimethylaminopropylidene) thiaxanthene hydrochloride.

EXAMPLE 6 2-meth0xy-7-chloro-10- [3-(4-morpholinyl) -pr0pyliden e] -thiaxanthene hydrochloride By replacing the 3-dimethylaminopropyl chloride and the 2-chlorothiaxanthone used in Example 2 by an equimolecular quantity of 3-(4-morpholinyl) -propyl chloride and Z-methoxy-lchlorothiaxanthone respectively, and following substantially the same procedures described in steps A and B of Example 2, there was obtained 2-methoxy-7-chloro-10-[3-(4 morpholinyl) propylidene] thiaxanthene hydrochloride.

EXAMPLE 7 3,8-di-propoxy-1 0-(S-dipropylaminopropylidene thiaxanthene hydrochloride By replacing the 3-dimethylaminopropyl chloride and the 2-chlorothiaxanthone used in Example 2 by an equimolecular quantity of 3-dipropylaminopropyl chloride and 3,8-dipropoxythiaxanthone respectively and following substantially the same procedures described in steps A and B of Example 2, there Was obtained 3,8-di-propoxy-l0-(3-dipropylaminopropylidene) thiaxanthene hydrochloride.

EXAMPLE 8 Z-ch l0ro-8-ethyl-1 O-(Z-methy l-3-dimethylamin opropy id cue) -thi axauth ene hydrochloride By replacing the 2-chlorothiaxanthone used in Example 2 by an equimolecular quantity of 2-chloro-8- ethylthiaxanthone, and following substantially the same procedures described in steps A and B of Example 2, there was obtained 2-chloro-8-ethyl-10-(2-methyl-3-dimethylaminopropylidene)-thiaxanthene hydrochloride.

EXAMPLE 9 Z-chloro-l 0-[3-(1-piperidyl) -propylidene] thiaxanlhene hydrochloride By replacing the 3-dimethylaminopropyl chloride used in Example 2 by an equimolecular quantity of 3-(l-piperidyl)-propyl chloride, and following substantially the same procedure described in steps A and B of Example 2, there was obtained 2-chlor0-10-[3-(1-piperidyl)- propylidene]-thiaxanthene hydrochloride.

EXAMPLE 10 7-propyl-10- [3- (1 -pyrrolidyl) -propylidene] thiaxanthene hydrochloride By replacing the S-dimethylaminopropyl chloride and the 2-chlorothiaxanthone used in Example 2 by an equimolecular quantity of 3-(l-pyrrolidyl)-propyl chloride and 7-propylthiaxanthone respectively, there was obtained 7 propyl l0 [3-( l-pyrrolidyl)-propylidene] -thiaxanthene hydrochloride.

EXAMPLE 11 aand fi-forms of Z-chloro-IO-(3-diethylaminopropylidene)-thiaxanthene hydrochloride Step A.The Grignard reagent was prepared from 4.86 g. (0.2 g. atom) of magnesium and 29.9 g. (0.2 mole) of 3-diethylaminopropyl chloride following essen tially the procedure described in step A of Example 2. The reaction mixture then was stirred and cooled in an ice-bath while 24.67 g. (0.1 mole) of 2-chlorothiaxanthone was added over a period of 10 minutes. The mixture then was allowed to warm up to room temperature and stirred at refluxing for 1 hour. The reaction mixture then was distilled until '75 m1. of distillate has been collected and the residue diluted with 150 ml. of benzene. The reaction mixture was hydrolysed in the cold by the dropwise addition of 70 ml. of 30% ammonium chloride solution. The benzene layer was separated by decantation and the gelatinous solid extracted with two m1. portions of benzene. The solid then was stirred with 50 ml. of 10 N sodium hydroxide, mixed with diatorn-aceous earth and the mixture filtered. The filtrate was extracted with 50 ml. of benzene and the combined benzene extracts washed with water and evaporated to dryness. The residue was an oily solid weighing 36.6 g., M.P. 108ll2 C. (sintering at The product was recrystallized from a mixture of benzene and hexane to give 29.75 g. (82%) of 2-chloro-10-(3-diethyl aminopropyl)-10-hydroxythiaxanthene, M.P. -1 17 C. Recrystallization f-rom mixtures of benzene and hexane yielded the product with a constant M.P. of 116.2 1l8.2 C.

Analysis-Calculated for C H ONClS: C, 66.37; H, 6.68; N, 3.87. Found: C, 66.14; H, 6.97; N, 3.87.

Step B.-The product obtained in step A, 7.24 g. (0.02 mole) was dissolved in 30 ml. of dry, alcohol-free chloroform and 4.72 g. (0.06 mole) of acetyl chloride added. The solution was refluxed for '1 hour and the solvent evaporated on the steam-bath under reduced pressure. The 2-chloro-10-(3-diethylaminopropylidene)-thiaxanthene hydrochloride was separated into the aand [it-forms by dissolving the residue in a mixture of absolute alcohol and absolute acetone and fractionally precipitating with absolute ether.

The a-form melted at 220.3-2223" C. after repeated recrystallization from a mixture of absolute ethanol and absolute ether.

Analysis-Calculated for C H NClS-HCl: C, 63.15; H, 6.09; N, 3.68. Found: C, 62.96; H, 6.13; N, 3.66.

The fi-form melted at 153.8155.3 C. after repeated recrystallization from acetone-ether mixtures.

Analysis.-Calculated for C H NClS-HCl: C, 63.15; H, 6.09; N, 3.68. Found: C, 63.12; H, 6.24; N, 3.65.

EXAMPLE 12 Z-metlzoxy-I 0- (3-dime thylaminopropylidene) -thiaxanthene hydrogen oxalate Step A.The Grignard reagent was prepared from 2.61 g. (0.107 mole) of magnesium and 13.05 g. (0.0539 mole) of 3-dimethylaminopropyl chloride in 50 ml. of dry tetrahydrofuran essentially as described in step A of Example 2. Z-methoxythiaxanthone, 13.00 g. (0.0537 mole), was added to the reaction mixture at 25 C. with stirring. After stirring for 15 minutes at room tempera ture, the mixture was heated to refluxing for 1 hour. The product was isolated following the procedure described in step A of Example 2. The yield of 2-methoxy-10-(3- dimethylaminopropyl) 10 hydroxythiaxanthene was 14.17 g. (80%) after recystallization from a mixture of benzene and hexane. Further recrystallization from mixtures of benzene and hexane yielded the product melting at 123124 C.

Analysis-Calculated for C H O NS: C, 69.26; H, 7.04; N, 4.25; S, 9.73. Found: C, 69.24; H, 6.98; N, 4.33; S. 9.61. 1

Step B.The product obtained in step A, 8.87 g. (0.0269 mole), was dissolved in 40 ml. of dry, alcoholfree chloroform and the solution treated with 6.35 g. (0.0809 mole) acetyl chloride. After refluxing the solution for one hour, the solvent was evaporated on the steam-bath under reduced pressure. The residue was dissolved in 50 ml. of water and the solution was made basic with 10, ml. of 5 N sodium hydroxide. The mixture was extracted with benzene. and the extract evaporated leaving the red oily b s Z-methoxy-lO-(S-dimethyl- 7 aminopropylidene)-thiaxanthene. The base was treated with oxalic acid in absolute alcohol solution and the hydrogen oxalate'precipitated by addition of absolute ether. After recrystallization from alcohol-ether mixtures the 2 methoxy-l-(3-dimethylaminopropylidene)-thiaxanthene hydrogen oxalate melted at 135-138 C. (sintered at 132 C.).

Analysis.Calculated for C H ONS-C H O -C,, 62.82; H, 5.77; N, 3.49. Found: C, 62.70; H, 5.87; N, 3.51.

EXAMPLE 13 2,8-dichl0ro-10- (3-dimethylaminopropylidene thiaxcmthene hydrochloride Step A.The Grignard reagent was prepared from 9.35 g. (0.384 g. atom) of magnesium and 46.7 g. (0.384 mole) of 3-dimethylaminopropyl chloride, using 3.3 g. of ethyl bromide and employing 150 m1. of tetrahydrofuran as solvent. The procedure of Example 2, step A was followed. To the Grignard solution was added 54 g. (0.192 mole) of 2,8-dichloro-thiaxanthone. After stirring at room temperature for 1 hour, the bulk of the tetrahydrofuran was distilled at reduced pressure keeping the temperature below 50 C. The residue was taken up in benzene and hydrolyzed in the cold by the dropwise addition of 75 ml. of water. The benzene layer was separated and the solid extracted with four 100 ml. portions of hot benzene. The combined benzene extracts were concentrated under reduced pressure and the residue crystallized from a mixture of benzene and hexane. The yield of product, 2,8-dichloro-10-(3-dimethylaminopropyl)-10-hydroxy thiaxanthene, M.P. 191.3-d92.3 C., was 46.6 g. The product from a similar experiment melted at 190.8- '191.8 C. after repeated crystallization from mixtures of benzene and hexane.

Analysis-Calculated for C H ONCl S: C, 58.70; H, 5.20; N, 3.80. Found: C, 58.77; H, 5.09; N, 3.79.

Step B.The thus obtained 2,8-dichloro1 0-(3-dimethylaminopropyl)-lO-hydroxy thiaxanthene, 7.2 g. (0.0195 mole), and 4.72 g. (0.06 mole) of 'acetyl chloride was dissolved in 30 ml. of alcohol-free chloroform. The solution was refluxed for one hour, then evaporated to dryness on the steam-bath under reduced pressure. The residual solid was taken up in hot alcohol, the solution cooled in ice and treated with 20% aqueous sodium hydroxide. The product solidified rapidly and was collected and dried at 70 C. to obtain 6.7 g. of crude 2,8-dichloro-l0'(3- dimethylam-inopropylidene)-thiaxanthene hydrochloride, M.P. 92-95 C. Recrystallization from a mixture of alcohol and water gave 525 g. of the purified product, M.P. 97.5-99.0" C. The pure product obtained in another experiment melted at 99100 C. (sintered'at 98 C.).

Analysis-Calculated for C H NCl S: C 61.71; H, 4.89; N, 4.00. Found: C, '6l.66; H, 4.94; N, 3.90.

EXAMPLE 14 2-m ethyl-1 0.- (3-d imethylamino pro pylidene) -thiaxanthene hydrochloride 2 -chl0ro-1 0- (3-dim ethy laminopropylidene) -thio.ranfhene hydrochloride Step A.-Magnesium turni-ngs, 6.07 g. (0.25 mole), were ground under benzene in a mortar and placed in a 500 ml. three-necked flask equipped with a mercury sealed stirrer, reflux condenser and dropping funnel. Ah-

solute ether, 110 ml.,. was added followed by 1.36 g. (0.013 mole) of ethylbromide. An atmosphere of hydrogen was maintainedin'the apparatus throughout the reaction. A solution :of 33.2 g. (0.2 mole) of 3dimethylam-inopropyl bromide in 1 46 ml. of absolute ether then was added at such a irate-that refiuxing was maintained. The addition required 35 minutes. 2-chlorothiaxanthone, 16.0: g. 1(105065 mole), :was added in portions of 4.0 g. at

7 intervals of 30 minutes. The reaction mixture then was refluxed for 1 hour. The reaction mixture was treated with 100 ml. of water with stirring and cooling, then diluted with 100 ml. of benzene and filtered through a mat of glass wool. The filter cake was extracted with three 100 ml. portions of hot benzene and the combined extracts evaporated to give 20.8 ,g. of crude 2-chloro-l0- (3-dimethylaminopropyl)-l0 hydroxythiaxanthene. The purified product was obtained by a process of recrystallization and extraction of the mother liquors by citric acid, the base was liberated from the citric acid solution by sodium hydroxide. The combined yield was 61%., M.P. 152-153 C.

Step B.-The thus obtained 2-chloro-10-(3-dimethylaminopropyl)-10-hydroxythiaxanthene was dehydrated by substantially the same procedure described in step B, EX- ample 2, to 2-chloro-l0-(3-dimethylaminopropylidene)- thiaxanthene hydrochloride.

EXAMPLE l6 Z-chloro-I O- (3-dimethylaminopropylidene thiaxanthene hydrochloride Step A.--The Grignard reagent was prepared from 6.07 g. (0.25 mole) of magnesium and 24.3 g. (0.2 mole) of dimethylaminopropyl chloride in 256 ml. of absolute ether following the procedure of Example 15. 2-chlorothiaxanthone, 24.67 g. (0.1 mole), was added in 5 portions at 30 minute intervals. The product was isolated substantially as described in Example 15. The yield of recrystallized 2 chloro-lO-(3-dimethylaminopropyl)-10- "hydroxythiaxanthene, M.P. 152.5154.0 C., was 15.24 g. (46%).

Step B.--The thus obtained 2-chloro-l0-(3-dimethylaminopropyl)-10-hydroxythiaxantheue was dehydrated by substantially the same procedure described in step 13, Example 2, to 2 chloro 10 .(B-dimethylaminopropylidene)-thiaxanthene hydrochloride.

While the invention has been illustrated to be particularly 10 (3 tertiaryaminopropylidene) -thiaxanthene compounds and particular methods for the preparation of these compounds, the invention embraces the chemical equivalents ofv the specifically identified compounds as well as the modifications of the methods described for their synthesis.

What is claimed is:

The process for preparing 10-(3-tertiaryamino-propyl)- 10hydr0xythiaxanthenes having the structure:

as defined above and the halide is selected from the group consisting of chlorine and bromine, magnesium and tetrahydrofuran, applying heat to maintain at refluxing temperature, then cooling to a temperature not higher than room temperature and adding to the resulting mixture 15 2,368,006

containing the Grignard reagent a thiaxanthenone having the structure:

in which X and X are as above defined, and adding water 10 to hydrolyze the resulting Grignard adduet to thereby obtain the desired product.

References Cited in the file of this patent UNITED STATES PATENTS Cusic Jan. 23, 1945 

